PD-1 Immunotherapy Combos May Be Next Step in Hodgkin Lymphoma Therapy

The prospect of combining PD-1 inhibitors with existing therapies, particularly brentuximab vedotin, is emerging as the most exciting new development in advancing the treatment of patients with Hodgkin lymphoma, raising the possibility of improving the cure rates in a disease where standard strategies have already produced notable results, according to Anas Younes, MD.

Younes, a medical oncologist who is chief of the Lymphoma Service at Memorial Sloan Kettering Cancer Center, is among the nation’s leading experts in developing new treatments for patients with Hodgkin and non-Hodgkin lymphomas. In an interview with OncLive, Younes said that nivolumab and pembrolizumab, which are both monoclonal antibodies targeting the PD-1 immune checkpoint, have demonstrated promise in early clinical trials among patients with Hodgkin lymphoma who have had multiple relapses.

“Both showed very good tolerance but also remarkable activity exceeding 60% or 70% response rates,” said Younes. “Some of these responses are really durable. This has generated tremendous excitement about further developing these agents and about the potential of combining them with other nonchemotherapeutic agents.”

When it comes to identifying partners for these immunotherapies, a regimen that would pair a PD-1 inhibitor with brentuximab “is the most exciting combination” to explore, said Younes. A phase I/II trial is scheduled to be launched combining brentuximab with nivolumab in an estimated 60 patients with relapsed or refractory Hodgkin lymphoma after failure of frontline therapy.1

“There is interest now in combining brentuximab vedotin with checkpoint inhibitors—two active agents,” he said. “Whether this will be sufficient by itself or would still need to be combined with chemotherapy would be the next step in drug development with Hodgkin lymphoma.” He said new combinations initially would be evaluated in the relapse setting and then tested in earlier lines of treatment. “It makes a lot of sense to combine them since each one has high single-agent activity,” Younes added. “We need to learn about the safety and efficacy of this combination.”

Strategies to Enhance Outcomes

Current Landscape

Standard therapies have improved outcomes dramatically during the past several decades for patients with Hodgkin lymphoma, a relatively rare cancer that is expected to result in an estimated 9000 new cases in the United States this year, according to the American Cancer Society.2 Approximately 95% of cases are categorized as classical Hodgkin lymphoma.

The overall 5-year and 10-year survival rates have reached 85% and 80%, respectively, with outcomes varying by stage. The 5-year survival rate is approximately 90% among patients with stages I or II disease, about 80% among individuals at stage III, and about 65% for patients at stage IV. Younes said about half of new patients are diagnosed at stages I or II, with the remainder presenting at the more advanced stages.

Those outcomes have been achieved with an armamentarium that includes first-line chemotherapy and radiation therapy regimens, and second-line autologous stem-cell transplantation (ASCT) therapy.

In 2011, the FDA approved brentuximab as a treatment for patients with relapsed Hodgkin lymphoma after the failure of ASCT or multiagent chemotherapy regimens; the antibody–drug conjugate that targets CD30 was the first new therapy approved for the malignancy since 1977. In August, brentuximab moved forward in the treatment timeline when the FDA approved a new indication for the agent to be used after ASCT consolidation therapy for patients at high risk of relapse or progression.

PD-1 Inhibitors

Nivolumab, which has gained FDA approvals in melanoma and non–small cell lung cancer (NSCLC), was designated as a breakthrough therapy in Hodgkin lymphoma in May 2014 after promising early clinical trial findings in patients with relapsed and refractory classical Hodgkin lymphoma.

In January 2015, Ansell et al reported that 20 of 23 patients (87%) with heavily pretreated Hodgkin lymphoma achieved an objective response to nivolumab therapy dosed at 3 mg/kg of body weight every 2 weeks, including 17% with a complete response.3 Most of the patients had previously been treated with ASCT and brentuximab.

The most frequently reported drug-related adverse events (AEs) of any grade were rash (22% of patients) and decreased platelet count (17%). Five patients (22%) experienced AEs of grade 3 severity, consisting of one AE in each of five categories: decreased lymphocyte count, increased lipase level, stomatitis, myelodysplastic syndrome, and pancreatitis.

Nivolumab has continued to demonstrate durable responses after more than a year of follow-up, researchers reported in June.4 The median duration of response for patients with Hodgkin lymphoma ranged from 9 weeks to more than 91 weeks.